tbuckley/cabot-search huggingface dataset:
IMMU-18. MIGRATION OF DENDRITIC CELLS THROUGH THE BRAIN-MENINGEAL LYMPHATIC-DRAINING LYMPH NODE NETWORK IN ORTHOTOPIC GLIOMA MODELS
Authors: Kristen Batich, Ching Wen Chen, Sebastian Wellford, Kianna Dao, Annie Park Moseman, Kelly Hotchkiss, Sarah Cook, David Snyder, John Sampson, Ashley Moseman
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Limited migration of dendritic cell (DC) vaccines to draining lymph nodes (DLN) remains a major limitation to DC efficacy for malignant gliomas. Our prior work demonstrated that increased peripheral DC migration to DLN results in enhanced antitumor efficacy. Given this, we studied DC trafficking in mouse gliomas, the meningeal lymphatic vessel (MLV) system, and the draining cervical lymph nodes (CLN). METHODS To elevate host DC populations, C57BL/6 and VMDk mice were implanted with B16-FMS-like tyrosine kinase 3 ligand (FLT3L) melanoma or with B16-FLT3L supernatant. Mice were implanted intracranially with CT2A, GL261-OVA, and SMA560 syngeneic glioma lines in the right parietal lobe. Antitumor efficacy was measured by tumor weights and median overall survival (mOS). RESULTS DC injected into glioma hemispheres display delayed kinetics of peak migration to CLN compared to control (7 days (d) vs 3d post-injection (pi), respectively). Migration of intraventricular (ivn)-injected DC to CLN is superior at days 1, 3 and 7 pi when glioma is present (p = 0.026). B16-FLT3L supernatant results in a disproportionate systemic expansion in conventional type 1 over type 2 DC (cDC1 &amp;gt; cDC2) compared to media control (cDC1, cDC2 fold change over media for spleen = 27,11; DLN = 6,2; blood = 6,3). Pulsed dosing of FLT3L supernatant results in significantly greater numbers of splenic cDC1 compared to daily FLT3L dosing (p = 0.002). Mice with CT2A and continuous FLT3L secretion in vivo show longer survival (mOS 30d) compared to mice with continuous GM-CSF secretion (mOS 22d) (p = 0.009). Mice with SMA560 and FLT3L secretion have significantly reduced glioma growth compared to tumor alone, GM-CSF-secreting tumors, and mixed FLT3L/GM-CSF-secreting tumors (p = 0.029). CONCLUSION FLT3L signaling in vivo results in cDC1 &amp;gt; cDC2 generation and migration through the CNS with more favorable glioma efficacy. Modeling of DC migration through the glioma-MLV-CLN system with FLT3L stimulation permits testing of strategies to improve DC therapy.
DDDR-36. VAL-083 IN PATIENTS WITH RECURRENT GLIOBLASTOMA TREATED UNDER EXPANDED ACCESS PROGRAM
Authors: Carlos Kamiya-Matsuoka, Nazanin Majd, Rebecca Harrison, Stephanie Knight, John Langlands, Dennis Brown, Vinay Puduvalli
Journal: Neuro-Oncology (2022)

Abstract Current standard-of-care for glioblastoma (GBM) includes surgery followed by radiation with concurrent and adjuvant temozolomide. There are limited treatment options available upon progression or recurrence of disease. Options often involve participation in clinical trials with promising new therapies. However, patients may not meet the strictly defined entry criteria to participate in these clinical trials. Under an Expanded Access (EA) program, we have treated 14 recurrent GBM patients with VAL-083, they were not eligible to participate in other clinical trials. The median time from last progression to start of VAL-083 was 1.0 month (95%CI:0.09-2.67). All patients had received chemoradiation with temozolomide. Five (5/14;36%) patients had ≥ 2 recurrences, 8/14 (57%) had multifocal disease, and the median KPS was 80 (95%CI:70-90). All patients had unmethylated MGMT promoter, 13/14 (93%) were IDH-WT, 9/14 (64%) had a TERT promoter mutation, 6/14 (43%) had a PTEN mutation, and 4/14 (28%) had an EGFR mutation. All patients received treatment with VAL-083 at 30 mg/m2 x 3 days every 21 days. Five patients with cerebral edema refractory to steroids received bevacizumab (BEV;10 mg/kg) concurrently with VAL-083, and 8 patients received dexamethasone (Dex; &amp;gt;4 mg/day) with VAL-083. This is the first report of the use of VAL-083 in combination with BEV (VAL-03/BEV).The main adverse event was thrombocytopenia consistent with prior experience. Four (4/14; 28%) patients had a dose reduction, 3 of which were due to thrombocytopenia. No patients had a dose reduction while receiving VAL-083/BEV. Two patients who progressed on VAL-083, were later treated with CCNU, and myelosuppression was not observed.Median progression-free survival (mPFS) and median overall survival (mOS) from last progression were 5.7 months (95%CI:1.3-7.9) and 8.3 months (95%CI:3.0-14.3), respectively. Additional treatment, safety and outcome data will be presented at the meeting.Clinicaltrials.gov Identifier: NCT03138629. EA treatment plans were approved by MD Anderson Cancer Center IRB.
BIOM-36. A STUDY OF CLINICAL AND MOLECULAR PROGNOSTIC FACTORS FOR RESPONSE TO REGORAFENIB IN RECURRENT GLIOBLASTOMA
Authors: Silvia Chiesa, Antonella Mangraviti, Maurizio Martini, Tonia Cenci, Ciro Mazzarella, Simona Gaudino, Serena Bracci, Antonella Martino, Giuseppe M Della Pepa, Martina Offi, Marco Gessi, Rosellina Russo, Matia Martucci, Francesco Beghella Bartoli, Rina Di Bonaventura, Luigi M Larocca, Liverana Lauretti, Alessandro Olivi, Roberto Pallini, Mario Balducci, Quintino Giorgio D'Alessandris
Journal: Neuro-Oncology (2022)

Abstract Introduction Following the results from the REGOMA study, regorafenib has become the first chemotherapeutic option for recurrent glioblastoma, IDH-wildtype, in many countries. However, predictive factors for response to regorafenib are scarcely recognized. The objective of this study was to identify molecular predictive factors for response to regorafenib using a clinically available platform. METHODS We analyzed a prospective cohort of 30 patients harboring recurrent glioblastoma, IDH-wildtype, and treated with regorafenib. Next-generation sequencing (NGS) analysis was performed on DNA extracted from paraffin-embedded tissues using a rapid, cheap, and clinically validated platform. MGMT methylation was assessed using methylation-specific PCR, and EGFRvIII expression was assessed using RT-PCR. RESULTS In our series, six-month progression-free survival (PFS) was 30% and median overall survival (OS) was 7.5 months: these data are consistent with current literature. Among clinical variables, gross-total resection was endowed with a positive prognostic value for PFS (p=0.0296, log-rank test). NGS analysis revealed a mutation in the EGFR pathway (EGFR and/or PIK3CA) in 18% of cases; a mutation in the mitogen-activated protein-kinase (MAPK) pathway (RAS and/or RET) in 18% of cases; no mutations in the remaining cases. Patients carrying MAPK pathway mutation had a poor response to regorafenib treatment, with a significantly shorter PFS and a nonsignificantly shorter OS compared to EGFR-mutated patients (for PFS, 2.5 vs 4.5 months, p=0.0061; for OS, 7 vs 9 months, p=0.1076). By combining NGS analysis with RT-PCR for EGFRvIII, we identified 14 patients with EGFR pathway activation, who had a significantly longer PFS and OS after regorafenib treatment. Multivariate analysis confirmed that MAPK pathway mutations predicted a scarce response to regorafenib treatment. Conclusions Through an easy-to-use and cheap platform, we identified a mesenchymal, MAPK-altered signature in IDH-wildtype glioblastoma, predictive of scarce response to regorafenib at recurrence. We thus provide a molecular selection criterion to implement in the clinical practice.
EXTH-97. BONE MARROW-DERIVED ENGINEERED MYELOID CELLS ENHANCE THE TRAFFICKING AND ACTIVATION OF CYTOTOXIC T CELLS IN THE GLIOMA MICROENVIRONMENT
Authors: Alessandro Canella, Matthew Nazzaro, Claire Schmitt, Sakthi Rajendran, Abigail Haffey, Giovanni Nigita, Diana Thomas, Prajwal Rajappa
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Gliomas are the most prevalent type of brain tumors in the adolescent and young adult population (AYA) and one of the leading causes of cancer- related death. Two-third of glioma AYA patients are affected by low-grade gliomas (LGGs), but yet there are no specific treatments. Therefore, a significant percentage of LGG patients experience tumor recurrence and malignant progression to high-grade glioma (HGG) and the immune microenvironment plays a critical role in mediating mechanisms of tumor progression and treatment resistance. Specifically, tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) have been shown to restrict cytotoxic effector trafficking and activation. To that end, first-line immunotherapies have limited efficacy in improving outcomes for HGGs. HYPOTHESIS We investigated the preclinical efficacy of a novel immunotherapeutic approach for the treatment of LGGs in AYA mice to modulate and reprogram the immunosuppressive tumor microenvironment (TME) and enhance the trafficking of activated effector T cells. METHODS Immunocompetent RCAS n/tv-a LGG bearing animals were treated at day 28 with a single retroorbital dose of bone-marrow derived myeloid cells, engineered for the release of Interlekin-2 (GEMys-IL2). The treatment was well tolerated and no sign of toxicity was noted. RESULTS Our results demonstrated that GEMys-IL2 efficiently crossed the BBB, infiltrate the glioma microenvironment, and activate infiltrating immune cells while altering the TME underscored by an increased CD8+ T cell population. Of note, the RCAS/t-va immunocompetent LGG to HGG progression mouse model treated with a single dose of GEMys-IL2 demonstrated a transient arrest of tumor burden within 14 days post treatment, which was associated with a significant advantage in overall survival. CONCLUSIONS These results highlight the pre-clinical efficacy and anti-tumoral therapeutic activity of GEMYys-IL2 on CD8+ T cell trafficking and activation to the TME in low-grade glioma in vivo, thus supporting its potential as a novel cell-mediated innate immunotherapy.
EPCO-32. HIGHLY MULTIPLEXED PROTEOGENOMIC SPATIAL PROFILING OF PEDIATRIC AND ADULT H3 K27-ALTERED DIFFUSE MIDLINE GLIOMAS
Authors: Sudarshawn Damodharan, Mahua Dey
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND H3 K27-altered diffuse midline gliomas (DMG) are highly aggressive malignancies of the central nervous system that affect both pediatric and adult populations. The immune layout and genetic changes within the tumor microenvironment associated with these high-grade malignancies are thought to play an integral role in the phenotypic differences in tumor presentation and clinical course between both populations. Comparative landscapes between pediatric and adult DMGs is not known. METHODS The NanoString GeoMxTM Digital Spatial Profiler platform was used to determine the immune marker and genetic layout in a cohort of both pediatric and adult H3 K27-altered DMG tissue samples. 5 samples from each population were assessed in triplicates for a total of 30 samples. Three fluorescently labeled antibodies targeting immune cells (CD45), epithelial cells (PanCK), tumor cells (H3 K27M) and a nucleic acid stain (SYTO-13) were used to identify and separate out the various components within the tumor tissues from selected regions of interest. The resultant information was then pooled into libraries that were run through the NanoString spatial profiler and Illumina sequencing system to assess proteomics and gene expressions for both cohorts of samples. RESULTS Our data revealed that there were immune and genetic changes that were seen within both populations across multiple regions of interest within the tumor tissues. A number of immune cell types and protein markers exhibited significant difference between the pediatric and adult tissue cohorts. CONCLUSION The proteogenomic spatial analysis of pediatric and adult H3 K27-altered DMG shows different immune and genetic profiles which are proposed to contribute to the clinical differences between both populations. These observed differences may play a role in future treatments for H3 K27-altered DMG and further research is needed to explore this.
EPID-09. AGE-STRATIFIED SURVIVAL ANALYSES OF CO-MORBIDITIES IN PATIENTS WITH GRADE IV GLIOMAS
Authors: Erik Rabin, Xinlei Mi, Jonathan Huang, Miri Kim, Andreas Mozny, Christina Amidei, Erica Sieg, April Bell, Lijie Zhai, Prashant Bommi, Kristen Lauing, Rimas Lukas, Derek Wainwright
Journal: Neuro-Oncology (2022)

Abstract Glioblastomas are the most common primary malignant brain tumor in adults. Subject age is a strong prognostic factor for survival. We performed a co-morbidity analysis of younger vs. older (greater than 65 years) adults with grade IV gliomas (GIV) to understand inherent differences that vary with subject age. Electronic health records for 1,208 GIV patients were collected at a single center between 1/1/2000 and 9/8/2021 and used to construct a multivariable time-dependent cox model that examined intra-cohort hazards associated with 33 measures of co-morbidity and tumor related symptoms. The date of GIV diagnosis was identified as the start time, and subject death was used to define event time. Patients that were alive or lost to follow-up were censored at the last recorded date. Survival time was calculated as the difference between diagnosis date and event time or censorship. GIV was stratified by IDH and MGMT promoter methylation status when available. Younger patients experienced a greater hazard with: limitations to movement (1.88 [1.46, 2.43] ****), gait (1.72 [1.17, 2.52] **), weakness (1.96 [1.26, 3.06] **), seizures (1.28 [1.04, 1.58] *), epilepsy (1.47 [1.09, 1.99] *), and anxiety disorders (2.37 [1.44, 3.92], **). Older GIV patients experienced an increased hazard with: confusion and altered mental status (4.3 [2.08, 8.89], ****). Both age groups experienced increases with eye/visual systems and plegia. These data indicate novel comorbid enrichments varying by subject age that, from a mechanistic perspective, may be used to better understand why older adults with GIV survive significantly less than younger counterparts.
DISP-15. TRENDS IN LASER INTERSTITIAL THERMAL THERAPY (LITT): HOW RACE AND SOCIOECONOMIC FACTORS IMPACT ACCESS
Authors: Danielle Terrell, Sandeep Kandregula, Joshua Caskey, Christopher Newman
Journal: Neuro-Oncology (2022)

Abstract Introduction This study seeks to examine the trends of laser interstitial thermal therapy (LITT) access in the pre-and post-Medicaid expansion time periods; and more specifically, how racial and socioeconomic factors impact access. Methods The National Inpatient Sample (NIS) database was queried for all patients who received LITT from 2010 to 2019 for any indication. Age, gender, race, payer status, and median income by zip code were obtained and compared for the pre-Medicaid expansion (2010-2014), and post-Medicaid expansion (2015-2019) groups. Chi-square analysis was performed for categorical variables, and the student t-test was used to analyze continuous variables. Results The pre-Medicaid expansion (n = 915) and post-Medicaid (n = 3205) time periods were similar in that Whites were the overwhelming majority of LITT recipients (78.7% and 70.8%, p &amp;lt; 0.001). In 2010, all races had low rates of LITT, as would be expected with a new emerging treatment. Although the absolute value of the percentages seems similar, between 2013 and 2014, the proportion of Whites receiving LITT nearly doubled (from 45% to 75%); while all other groups had no significant increase in utilization. Utilization of LITT by Black Americans remained stable, 5.4% and 5.6% in the pre- and post-Medicaid expansion eras, while Hispanics and Others saw slight increases in utilization (8.8% to 10.1% and 7.1% to 13.4% respectively). Although Medicare and Medicaid usage increased over the years, private insurance remained the primary payer for LITT (53.8% and 49.3%, p 0.018). Lastly, patients within the highest income quartiles comprised over half of LITT procedures done in the study period (56.8% and 52.8%, p 0.029). Conclusion Despite nearly a decade and the effects of Medicaid expansion via the Affordable Care Act, LITT is still difficult to access for patients of color, Medicare and Medicaid users, and patients in low-income locales.
EOLP-05. POSTMORTEM TISSUE DONATION: GIVING FAMILIES THE ABILITY TO CHOOSE
Authors: Vijay Ramaswamy, Nicole Lyons, Elizabeth Frenkel, Elena Gerismov, Allen Gustafson, Patti Gustafson, Ginny McLean, Aloysius Ochasi, Angela Waanders
Journal: Neuro-Oncology (2022)

Abstract To our knowledge, Gift From a Child (GFAC) is the only dedicated consortium providing autopsy resources for children with brain tumors. Using the parental data and the experience of being a multi-institutional post mortem CNS tumor collection program, GFAC seeks to inform medical professionals of the need to approach families about post-mortem donation and demonstrate how barriers to donation can be overcome. Much like the one that occurred for organ donation, a cultural shift is needed with the goal to offer every family the option to donate. Collected survey data shows, 98% of families who donated were satisfied with their decision, compared to 20% of families who did not donate being satisfied with their decision. Most families want to be provided the opportunity to chooseto donate, citing the desire to advance research and help future families. For families who donated, over 71% initiated the donation conversation with their clinician. Among those who did not donate, 58% reported they had not been asked. The healthcare team initiated the donation conversation only 20% of the time for both groups. Without the conversation being initiated, many families remain unaware of the necessity and impact of donation on advancing research. The timing and structure of how donation is brought up impacts if families proceed with donating, however, data shows that withholding this option is frequently more distressing for families. Parent interviews and survey data indicate the majority of families are most open to this conversation once it’s evident a child will not survive and during transition to hospice care. Presentation donation as a driver for research, helping the next child, and as a key step in the family’s grieving process positively correlate with a family’s decision to donate.
EPCO-21. THE SPATIAL ORGANIZATION OF H3-K27M MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Ilon Liu, Jiang Li, Erik Samuelsson, Sergio Marco Salas, Alexander Beck, Olivia Hack, Daeun Jeong, McKenzie Shaw, Bernhard Englinger, Jenna Labelle, Hafsa Mire, Sibylle Madlener, Lisa Mayr, Michael Quezada, Maria Trissal, Eshini Panditharatna, Kati Ernst, Taylor Gatesman, Matthew Halbert, Hana Palova, Petra Pokorna, Jaroslav Sterba, Ondrej Slaby, Rene Geyeregger, Aaron Diaz, Adam C Resnick, Mario Suva, David Jones, Sameer Agnihotri, Jessica Ostlin, Carl Koschmann, Christine Haberler, Thomas Czech, Irene Slavc, Jennifer Cotter, Keith Ligon, Sanda Alexandrescu, W K Alfred Yung, Isabel Arrillaga-Romany, Johannes Gojo, Michelle Monje, Mats Nilsson, Mariella Filbin
Journal: Neuro-Oncology (2022)

Abstract Histone 3 lysine27-to-methionine mutant diffuse midline gliomas (H3-K27M DMGs) are among the most lethal brain tumors. Their putative cellular hierarchy has been shown to be driven by self-renewing stem-like cells arrested in an oligodendrocyte precursor-like (OPC-like) state, of which few cells are able to differentiate towards more mature astrocyte (AC)-like and oligodendrocyte (OC)-like cells. However, the spatial organization underlying this tumor cell architecture and its microenvironmental interactions in intact H3-K27M DMG tissues remain unknown. Here, we profiled the single cell transcriptomes of 45 patient H3-K27M DMGs and derived cell population-specific marker gene combinations to characterize the single cell spatial organization of 16 tumors using targeted in situ sequencing. We thereby resolved different malignant and non-malignant cell populations including cycling, OPC-like, AC-like, OC-like, mesenchymal tumor cells, and non-malignant oligodendrocytes, astrocytes, neurons, myeloid cells, T cells, and vascular cells directly in situ. Global neighborhood analyses indicate a higher tendency of cycling OPC-like cells, vascular cells, and neurons to localize within a more restricted homogeneous compartment, whereas AC-like cells, non-malignant astrocytes and myeloid cells tend to intermingle with different cell populations in a more diffuse manner. Among malignant cells, we observed cycling OPC-like and OC-like cells to co-localize within a niche-like structure that is surrounded by more differentiated AC-like cells. We further validated this stem-like niche at the protein level using multiplexed immunofluorescence via the CODEX system. Finally, we characterized relationships between malignant and non-malignant cells, consistently identifying preferred neighborhoods of mesenchymal tumor cells with vascular and myeloid cells. Together, this study resolves the spatial architecture of H3-K27M DMG malignant and non-malignant cells at single cell resolution and identifies a local niche of the oligodendroglial lineage containing the OPC-like cancer stem-like cells, thus providing novel insights into the cancer stem-like compartment in H3-K27M DMGs and suggesting potential avenues for its perturbation.
BIOM-29. THE PROGNOSTIC AND PREDICTIVE SIGNIFICANCE OF PARTIAL MGMT PROMOTER METHYLATION FOR IDH-WILDTYPE GLIOBLASTOMA PATIENTS
Authors: Matthew Torre, Bryan Iorgulescu
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma patients showing hypermethylation of the promoter of the O6-methylguanine-methyltransferase (MGMT) gene have significantly improved survival when treated with temozolomide compared to patients with hypomethylated MGMT promoters. However, the prognostic and predictive significance of partial MGMT promoter methylation is unclear. METHODS The National Cancer Database was queried for patients newly diagnosed in 2018 with histopathologically-confirmed IDH-wildtype glioblastoma. MGMT promoter methylation status was correlated with overall survival (OS) using multivariable Cox regression with Bonferroni correction for multiple testing (p&amp;lt; 0.008 was significant). RESULTS 3,663 patients were identified with newly diagnosed, histopathologically-confirmed IDH-wildtype glioblastoma and known MGMT promoter methylation. Of the 2,807 patients who received single agent chemotherapy (i.e. likely temozolomide), the MGMT promoter was unmethylated, partially methylated, hypermethylated, and methylated not otherwise specified (NOS) in 57.9%, 5.0%, 3.1%, and 34.0% of cases, respectively, with the later group likely consisting predominantly of hypermethylated cases. Multivariable analysis demonstrated that among patients receiving temozolomide, those with unmethylated MGMT promoters had significantly worse OS than patients with partially methylated MGMT promoters (hazard ratio (HR) 1.94; 95% confidence interval (CI), 1.54-2.44; p&amp;lt; 0.001). However, the OS of hypermethylated patients (HR 1.02; 95% CI, 0.72-1.46; p=0.9) and methylated NOS patients (HR 0.99; 95% CI, 0.78-1.26; p=0.928) were not statistically different from the OS of partially methylated patients. CONCLUSIONS IDH-wildtype glioblastoma patients with partial methylation of the MGMT promoter treated with temozolomide have improved OS compared to their unmethylated counterparts, supporting the use of temozolomide therapy in these patients.